Systemic sclerosis (“SSc”) is a connective tissue disease characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (“ECM”) (1). The mechanism(s) resulting in fibrosis in SSc are still under investigation. It has been reported that fibronectin (“FN”) mRNA levels in SSc dermal fibroblasts are up to ten-fold greater than those in healthy donors (26, 31). Thus FN, a key component of ECM, is abnormally expressed in SSc. There are currently no effective treatments to prevent or halt the progression of fibrosis in SSc and other fibrosing diseases (2).
SSc has a worldwide distribution and is more frequent in women than men (3). The female:male ratio is approximately 3:1. Surprisingly, the ratio increases to 10:1 during the child-bearing years (1). This suggests that female sex hormones such as estrogens and progesterone may contribute to disease pathogenesis.
Estrogens, especially estradiol (“E2”), play an important role in many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition and behavior (3). Given this widespread role for E2 in human physiology, E2 is also implicated in the development or progression of numerous diseases, including various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, endometriosis, and obesity (36, 37, 38, 39, 40). In many of these diseases, estrogen mediates its effects through estrogen receptors (“ERs”), which serve as the targets for many therapeutic interventions.
The clinical effects of hormone replacement therapy (“HRT”) and tamoxifen, a selective estrogen receptor modulator (“SERM”) have been evaluated in SSc patients (24, 25). HRT was suggested to exert protective effects against the development of isolated pulmonary hypertension in patients with SSc and limited cutaneous involvement (24). Tamoxifen, largely used as an estrogen receptor inhibitor but which has conditional agonist activity, did not improve SSc symptoms (25). Cyclofenil, another SERM which has found use as an anabolic steroid by body builders, has also been explored as a potential treatment for SSc with disappointing results (57).